Page 809 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

768 SECTION | XI Bacterial and Cyanobacterial Toxins

VetBooks.ir TABLE 57.1 (Continued) Toxins

Cyanobacterial Species
Synechocystis spp. Anatoxin-a, microcystins
Tolypothix byssoidea Cytotoxin
Trichodesmium erythraeum Neurotoxin
Trichodesmium thiebautii Microcystins, neurotoxins
Trichormus variablis Anatoxin-a
Umezakia natans Cylindrospermopsin
Woronichinia naegeliana Anatoxin-a

microcystin-LR, has been found worldwide and has in the small intestine (Ito et al., 2000); thus, the integrity
caused acute, lethal hepatotoxicoses in farm animals of the intestinal mucosa can significantly impact the
(Carbis et al., 1994; Mez et al., 1997; Puschner et al., degree of absorption (Zeller et al., 2011). Altered cell per-
1998) and hepatic injury in humans (Azevedo et al., meability of the small intestine in aged mice lends them
2002; Rao et al., 2002). more susceptible than young animals (Ito et al., 1997).
Once absorbed, microcystins are rapidly distributed to the
liver (Runnegar et al., 1981; Fischer et al., 2000), but they
Pharmacokinetics/Toxicokinetics can also reach lung, heart, and capillaries (Ito et al.,
2000). Based on radiolabeled experiments in which
Despite the abundant literature on microcystins, under- microcystins were administered i.v. in Wistar rats, uptake
standing of pharmacokinetics remains limited, particularly into the kidney appears to be important for excretion.
with regard to potential species variations. Most studies Results of uptake experiments with radiolabeled dihydro-
have been conducted in mice after intravenous (i.v.) and MC-LR demonstrated that OATP1B1 (organic anion
intraperitoneal (i.p.) administration of cyanobacteria, their transporter protein) and OATP1B3 are involved in uptake
filtrates, and, in some instances, purified microcystins. of MC-LR (Seithel et al., 2007). Studies in fish (i.v.) have
After i.v. and i.p. administration in mice and rats, micro- demonstrated that the liver is the primary target, followed
cystins are rapidly distributed to the liver (Falconer et al., by kidney and gonads, although uptake does occur into
1986; Robinson et al., 1991). Plasma half-lives of muscle tissue and cardiovascular effects are observed
microcystin-LR in mice after i.v. administration were 0.8 (Malbrouck and Kestemont, 2006). Absorption of micro-
and 6.9 min for the alpha and beta phases of elimination cystin via the respiratory route (Ito et al., 2001) has been
(Robinson et al., 1991). Interestingly, the hepatic concen- demonstrated to lead to lethality in mice and also induce
3
tration of H-microcystin-LR remained constant through- damage to nasal epithelium at lower exposures (Benson
out the 6-day study, indicating accumulation in this target et al., 2005), thus posing a threat from aerosolization of
organ. This study also demonstrated that approximately the compound.
9% and 14% of the dose was excreted in urine and feces,
respectively, after 12 h, with 60% of it being excreted
unchanged. Additional studies in swine have also indi- Mechanism of Action
cated that the majority is excreted unchanged, with only
two metabolites detected; biliary excretion is also noted Specifically toxic to liver, microcystins cause severe
after less than 1 h of i.v. administration (Stotts et al., hepatomegaly macroscopically and progressive centrilob-
1997). The exact route of metabolism is yet to be defined, ular hepatocyte rounding, dissociation, and necrosis
but glutathione and cysteine conjugation have been identi- microscopically. Breakdown of the sinusoidal endothe-
fied and may represent major detoxification pathways lium and intrahepatic hemorrhage ultimately result in
(Kondo et al., 1996; Pflugmacher et al., 1998). Other death (Hooser et al., 1991a; Falconer and Yeung, 1992).
metabolites have been identified in vivo and in vitro, but Unable to permeate cell membranes, microcystins enter
further work is needed to define their roles. hepatocytes via the bile acid transporter mechanism
Data on bioavailability for microcystins are needed to (Hooser et al., 1991b). Once inside the hepatocytes,
better evaluate risk from oral ingestion. Absorption occurs microcystins are potent inhibitors of protein phosphatases